Cancer Cell–Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma

Abstract

The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell-derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SER-PINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell-derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell-derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets.Significance: This study provides insights into the biological roles of cancer cell-derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

SWATH-MS based proteomic profiling of pancreatic ductal adenocarcinoma tumours reveals the interplay between the extracellular matrix and related intracellular pathways

“…In this study, we observed that pathways involved in ECM formation and interactions were dysregulated corroborating the findings of several studies [33][34][35][36]. The ECM modulates intracellular signalling pathways; consequently, aberrant ECM homeostasis and ECM remodelling can induce and enhance tumorigenesis.…”

Expression Profiling of Extracellular Matrix Genes Reveals Global and Entity-Specific Characteristics in Adenoid Cystic, Mucoepidermoid and Salivary Duct Carcinomas

“…Additionally, we included 5 supplementary carcinomas of each tumour entity that were not analysed with the Nanostring method. As ECM production by tumour cells has also been reported [ 11 , 13 ], we used RNA in situ hybridisation (RNA-ISH) for COL11A1 and COL27A1 ( Figure 3 ).…”

“…Matrix protein production by tumour cells has been noted in other primaries [ 12 , 13 , 62 ]. Recently, ECM protein expression in pancreatic ductal carcinoma cells, rather than in stromal cells, has been shown to correlate with poor prognosis [ 13 ]. Surprisingly, in case of AdCy, we hardly noticed any COL11A1 + CAFs in the TME, which is in contrast to the abundance of CAFs in the other two entities.…”

“…This organ- and context-specific network [ 4 ] is gradually altered throughout tumour initiation [ 5 , 6 , 7 , 8 ], progression and metastasis [ 9 , 10 ] as it provides a niche for tumour cell survival [ 4 , 11 ]. It is considered to be mainly secreted by cancer-associated fibroblasts (CAF) but tumour cells also seem to produce ECM molecules [ 12 , 13 ]. High ratios of the resulting peritumoural stroma have been associated with an adverse outcome in a multitude of primaries [ 14 ].…”

Pancreatic Adenocarcinoma Invasiveness and the Tumor Microenvironment: From Biology to Clinical Trials

“…Whereas most ECM proteins are secreted by the pancreatic tumor stromal cells, a small subset is secreted by PDAC cells [ 140 ]. Interestingly, PDAC-derived matrisomal components such as serpin B5 and cystatin B promote metastasis through invadopodia formation and intravasation in AsPC1 pancreatic cancer cells [ 141 ]. These findings suggest that strategies that selectively target cancer-cell derived stromal components may have therapeutic benefit in PDAC.…”